Analysis of seven maternal polymorphisms of genes involved in homocysteine/folate metabolism and risk of Down syndrome offspring

Genet Med. 2006 Jul;8(7):409-16. doi: 10.1097/01.gim.0000228206.21793.82.


Purpose: We present a case-control study of seven polymorphisms of six genes involved in homocysteine/folate pathway as risk factors for Down syndrome. Gene-gene/allele-allele interactions, haplotype analysis and the association with age at conception were also evaluated.

Methods: We investigated 94 Down syndrome-mothers and 264 control-women from Campania, Italy.

Results: Increased risk of Down syndrome was associated with the methylenetetrahydrofolate reductase (MTHFR) 1298C allele (OR 1.46; 95% CI 1.02-2.10), the MTHFR 1298CC genotype (OR 2.29; 95% CI 1.06-4.96), the reduced-folate-carrier1 (RFC1) 80G allele (1.48; 95% CI 1.05-2.10) and the RFC1 80 GG genotype (OR 2.05; 95% CI 1.03-4.07). Significant associations were found between maternal age at conception > or = 34 years and either the MTHFR 1298C or the RFC 180G alleles. Positive interactions were found for the following genotype-pairs: MTHFR 677TT and 1298CC/CA, 1298CC/CA and RFC1 80 GG/GA, RFC1 80 GG and methylenetetrahydrofolate-dehydrogenase 1958 AA. The 677-1298 T-C haplotype at the MTHFR locus was also a risk factor for Down syndrome (P = 0.0022). The methionine-synthase-reductase A66G, the methionine-synthase A2756G and the cystathionine-beta-synthase 844ins68 polymorphisms were not associated with increased risk of Down syndrome.

Conclusion: These results point to a role of maternal polymorphisms of homocysteine/folate pathway as risk factors for Down syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Case-Control Studies
  • Chromosome Aberrations
  • Down Syndrome / genetics*
  • Female
  • Folic Acid / metabolism*
  • Gene Frequency
  • Genotype
  • Haplotypes
  • Homocysteine / metabolism*
  • Humans
  • Maternal Age
  • Membrane Transport Proteins / genetics*
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Models, Biological
  • Polymorphism, Genetic*
  • Risk Factors


  • Membrane Transport Proteins
  • SLC19A2 protein, human
  • Homocysteine
  • Folic Acid
  • Methylenetetrahydrofolate Reductase (NADPH2)